Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors

ABSTRACT

This invention relates to compounds of formula (I): ##STR1## which are useful as modulators of D 3  receptors, in particular in the treatment of psychoses.

This application is a 371 of PCT/EP97/02434 filed May 6, 1997.

The present invention relates to novel tetrahydroisoquinolinederivatives, processes for their preparation, pharmaceuticalcompositions containing them and their use in therapy, as modulators ofdopamine D₃ receptors, in particular as antipsychotic agents.

U.S. Pat. No. 5,294,621 describes tetrahydropyridine derivatives of theformula: ##STR2## wherein ##STR3## is an optionally substituted thienylor optionally substituted phenyl ring; R¹, R² and R³ are each inter aliahydrogen; X is inter alia (CH₂)mNR⁷ CO; m is 2-4; and Ar¹ is anoptionally substituted heterocyclic ring or an optionally substitutedphenyl ring. The compounds arm said to be useful as antiarrhythmicagents.

We have now found a class of tetrahydroisquinoline derivatives whichhave affinity for dopamine receptors, in particular the D₃ receptor, andthus potential in the treatment of conditions wherein modulation of theD₃ receptor is beneficial, eg as antipsychotic agents.

In a first aspect the present invention provides compounds of formula(I): ##STR4## wherein: R¹ represents a substituent selected from: ahydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethanesulfonyloxy, C₁₋₄ alkyl, C₁₋₄ alkoxy,arylC₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkoxyC₁₋₄ alkyl, C₃₋₆cycloalkylC₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄alkylsulphonyl, C₁₋₄ alkylsulphonyloxy, C₁₋₄ alkylsulphonylC₁₋₄ alkyl,arylsulphonyl, arylsulphonyloxy, arylsulphonylC₁₋₄ alkyl, C₁₋₄alkylsulphonamido, C₁₋₄ alkylamido, C₁₋₄ alkylsulphonamidoC₁₋₄ alkyl,C₁₋₄ alkylamidoC₁₋₄ alkyl, arylsulphonamido, arylcarboxamido,arylsulphonamidoC₁₋₄ alkyl, arylcarboxamidoC₁₋₄ alkyl, aroyl, aroylC₁₋₄alkyl, or arylC₁₋₄ alkanoyl group; a group R³ OCO(CH₂)_(p), R³CON(R⁴)(CH₂)_(p), R³ R⁴ NCO(CH₂)_(p) or R³ R⁴ NSO₂ (CH₂)_(p) where eachof R³ and R⁴ independently represents a hydrogen atom or a C₁₋₄ alkylgroup or R³ R⁴ forms part of a C₃₋₆ azacyloalkane or C₃₋₆(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to4; or a group Ar² --Z, wherein Ar² represents an optionally substitutedphenyl ring or an optionally substitted 5- or 6-membered aromaticheterocyclic ring and Z represents a bond, O, S, or CH₂ ;

R² represents a hydrogen atom or a C₁₋₄ alkyl group;

q is 1 or 2;

Ar and Ar¹ each independently represent an optionally substituted phenylring or an optionally substituted 5- or 6-membered aromatic heterocyclicring; and

Y represents a bond, --NHCO--, --CONH--, --CH₂ --, or --(CH₂)_(m) Y¹(CH₂)_(n) --, wherein Y¹ represents O, S, SO₂, or CO and m and n eachrepresent zero or 1 such that the sum of m+n is zero or 1;

and salts thereof.

In the compounds of formula (I) above an alkyl group or moiety may bestraight or branched. Alkyl groups which may be employed include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and any branched isomersthereof such as isopropyl, t-butyl, sec-pentyl, and the like.

When R¹ represents an arylC₁₋₄ alkoxy, arylsulphonyl, arylsulphonyloxy,arylsulphonylC₁₋₄ alkyl, arylsulphonamido, arylcarboxamido,arylsulphonamidoC₁₋₄ alkyl, arylcarboxamidoC₁₋₄ alkyl, aroyl, aroylC₁₋₄alkyl, or arylC₁₋₄ alkanoyl group, the aryl moiety may be selected froman optionally substituted phenyl ring or an optionally substituted 5- or6-membered heterocyclic ring. In the group R¹ an aryl moiety may beoptionally substitued by one or more substituents selected fromhydrogen, halogen, amino, cyano, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄dialkylamino, C₁₋₄ alkylamido, C₁₋₄ alkanoyl, or R⁵ R⁶ NCO where each ofR⁵ and R⁶ independently represents a hydrogen atom or C₁₋₄ alkyl group.

A halogen atom present in the compounds of formula (I) may be fluorine,chlorine, bromine or iodine.

When q is 2, the substituents R¹ may be the same or different.Preferably q represents 1.

An optionally substituted 5- or 6-membered heterocyclic aromatic ring,as defined for either of the groups Ar, Ar¹ or Ar² may contain from 1 to4 heteroatoms selected from O, N or S. When the ring contains 2-4heteroatoms, one is preferably selected from O, N and S and theremaining heteroatoms are preferably N. Examples of 5 and 6-memberedheterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl,triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.

The rings Ar, Ar¹ or Ar² may each independendy be optionally substitutedby one or more substituents selected from: a hydrogen or halogen atom,or a hydroxy, cyano, nitro, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄alkylsulphonyl, C₁₋₄ alkylaminosulphonyl or C₁₋₄ dialkylaminosulphonylgroup.

Alternatively, Ar¹ may be optionally substituted by one or moresubstituents selected from: a 5- or 6-membered heterocyclic ring, asdefined above, optionally substituted by a C₁₋₂ alkyl group; a group--CONR⁷ R⁸, R⁷ R⁸ NSO2--, or R⁷ CON(R⁸)--wherein each of R⁷ and R⁸independently represents a hydrogen atom or a C₁₋₄ alkyl group, or R⁷ R⁸together form a C₃₋₆ alkylene chain. Substituents positioned ortho toone another may be linked to form a 5- or 6-membered ring.

It will be appreciated that for use in medicine the salts of formula (I)should be physiologically acceptable. Suitable physiologicallyacceptable salts will be apparent to those skiled in the art and includefor example acid addition salts formed with inorganic acids eg.hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; andorganic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonicacid. Other non-physiologically acceptable salts eg. oxalates, may beused, for example in the isolation of compounds of formula (I) and areincluded within the scope of this invention. Also included within thescope of the invention are solvates and hydrates of compounds of formula(I).

Particular compounds according to the invention include:

7-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinolineN-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydmuisoquinoline;

7-Methylsulfonyloxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

7-(4-(3,5-Dimethyl)isoxazolyl)sulfonyloxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Methoxy-2-(4-(4-(6-methyl)-3-pyridyl)benzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Aminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(1-Methyl-4-pyrazolyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazolyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-Pyrimidyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-(1-(2-Oxo)pyrrolidinyl)phenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Arminosulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(5-(1-Oxo)indanyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(3-(6-(1-Pyrrolyl)pyridyl)carboxamido)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrmhydroisoquinoline;

2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazolyl)-phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-(5-Methyl-1,3,4-oxadiazolyl)phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Methylaznnocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline:

2-(4-(4-(4-Pyridyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(2-(5-(2-Pyridyl)thienylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-pyridyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(Phenylbenzoylamino)butyl)-7-(3-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

7-Methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Ethoxycarbonylmethyl-2-(4-(4-phenylbenzoylarino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-(2-Cyanophenoxy)-2-(4-(4-phenylbenzoylamino)butyl-1,2,3,4-tetrahydroisoquinoine;

7-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Cyano-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline;

and salts thereof.

The present invention also provides a process for preparing compounds offormula (I) which process comprises:

(a) reacting a compound of formula (II): ##STR5## wherein R¹ and q areas hereinbefore defined; with a compound of formula (III): ##STR6##wherein R², Y, Ar and Ar¹ are as hereinbefore defined; (b) reaction of acompound of formula (IV): ##STR7## wherein R¹ and R² are as hereinbeforedefined; with a compound of formula (V):

    Ar.sup.1 --Y-ArCOX                                         Formula (V)

wherein Y, Ar and Ar¹ art as hereinbefore defined and X is a halogenatom or the residue of an activated ester;

(c) to prepare a compound of formula (I) wherein R¹ is Ar² --Z and Z isa bond, reacting a compound of formula (VI): ##STR8## wherein one R^(1a)represents a group W wherein W is a halogen atom or atrifluoromethylsulphonyloxy group, or W is a group M selected from aboron derivative e.g. a boronic acid function B(OH)₂ or a metal functionsuch as trialkylstannyl e.g. SnBu₃, zinc halide or magnesium halide, andwhen q is 2 the other R^(1a) is R¹ ; with a compound Ar² --W¹, whereinW¹ is a halogen atom or a trifluoromethylsulphonyloxy group when W is agroup M or W¹ is a group M when W is a halogen atom or atrifluoromethylsulphonyloxy group;

(d) to prepare a compound of formula (I) wherein R¹ is Ar² --Z and Z isO or S, reacting a compound of formula (VII): ##STR9## wherein oneR^(1b) represent a group ZH and when q is 2 the other R^(1b) representsR¹ ; with a reagent serving to introduce the group Ar² ;

(e) to prepare a compound of formula (I) where Y is a bond, reaction ofa compound of formula (VIII): ##STR10## wherein R¹, R², Ar and W are ashereinbefore defined, with a compound Ar¹ --W¹, wherein W¹ is a halogenatom or a trifluoromethylsulphonyloxy group when W is a group M, or W¹is a group M when W is a halogen atom or a trifluoromethylsulphonyloxygroup.

(f) interconversion of one compound of formula (I) to a differentcompound of formula (I) e.g. (i) alkylation of a compound (I) wherein R²represents hydrogen, (ii) conversion of one R¹ from alkoxy (e.g.methoxy)to hydroxy, or (iii) conversion of R¹ from hydroxy to sulphonyloxy, egalkylsulphonyloxy or trifluoromethanesulphonyloxy; (iv) conversion of acompound wherein Y represents S to a compound wherein Y is SO₂ or (v)conversion of Y from CO to CH₂ ; and optionally thereafter forming asalt of formula (I).

Process (a) requires the presence of a reducing agent. Suitable reducingagents which may be employed include sodium borohydride,cyanoborohydride or triacetoxyborohydride under acidic conditions, orcatalytic hydrogenation. The reaction may conveniently be effected in asolvent such as ethanol.

Process (b) may be effected by methods well known in the art forformation of an amide bond.

Reaction of a compound of formula (VI) with Ar² W¹, according to process(c) or a compound of formula (VIII) with Ar¹ --W¹ according to process(e) may be effected in the presence of a transition metal eg palladiumcatalyst such as bis-triphenylphosphinepalladium dichloride ortetrakis-triphenylphosphinepalladium (0). When M represents a boronicacid function such as B(OH)₂ the reaction may be carried out under basicconditions, for example using aqueous sodium carbonate in a suitablesolvent such as dioxane. When M is trialkylstannyl the reaction may becarried out in an inert solvent, such as xylene or dioxane optionally inthe presence of LiCl. When M is a zinc or magnesium halide the reactionmay be effected in an aprotic solvent such as tetrahydrofuran. Thesubstituent W is preferably a halogen atom such as bromine, or asulphonyloxy group such as trifluoromethylsulphonyloxy; and W¹ ispreferably a group M, such as trialkylstannyl or B(OH)₂.

In process (d) the reagent serving to introduce the group Ar² ispreferably a compound of formula Ar² --Hal, wherein Hal is a halogenatom. The reaction may be effected in the presence of a base, such aspotassium carbonate, in a solvent such as dimethylformamide.

Interconversion reactions according to process (e) may be effected usingmethods well known in the art.

Compounds of formula (II) may be prepared by methods known in the art.

Compounds of formula (III) are known or may be prepared using standardprocedures.

A compound of formula (IV) may be prepared by alkylation of a compound(II) by standard methods. Thus, for example a compound of formula (II)may be reacted with N-(4-bromobutylphthalimide) followed by removal ofthe phthalimide group to give a compound of formula (TV) where R² ishydrogen. Compounds where R² is alkyl may be prepared by subsequentreaction with the appropriate aldehyde using conditions analogous toprocess (a) above.

Compounds of formula (VI), (VII) or (VIII) may be prepared by processesanalogous to (a) or (b) described above. Compounds Ar¹ W¹, Ar² W¹ andAr² Hal are commercially available or may be prepared by standardmethods.

Compounds of formula (1) have been found to exhibit affinity fordopamine receptors, in particular the D₃ receptor, and are expected tobe useful in the treatment of disease states which require modulation ofsuch receptors, such as psychotic conditions. Compounds of formula (I)have also been found to have greater affinity for dopamine D₃ than forD₂ receptors. The therapeutic effect of currently availableantipsychotic agents (neuroleptics) is generally believed to be exertedvia blockade of D₂ receptors; however this mechanism is also thought tobe responsible for undesirable extrapyramidal side effects (eps)associated with many neuroleptic agents. Without wishing to be bound bytheory, it has been suggested that blockade of the recentlycharacterised dopamine D₃ receptor may give rise to beneficialantipsychotic activity without significant cps. (see for exampleSokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, ClinicalNeuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds ofthe present invention are therefore those which have higher affinity fordopamine D₃ than dopamine D₂ receptors (such affinity can be measuredusing standard methodology for example using cloned dopamine receptors).Said compounds may advantageously be used as selective modulators of D₃receptors.

We have found that certain compounds of formula (I) are dopamine D₃receptor antagonists, others may be agonists or partial agonists. Thefunctional activity of compounds of the invention (i.e. whether they areantagonists, agonists or partial agonists) can be readily determinedusing the test method described hereinafter, which does not requireundue experimentation. D₃ antagonists are of potential use asantipsychotic agents for example in the treatment of schizophrenia,schizo-affective disorders, psychotic depression and mania. Conditionswhich may be treated by dopamine D₃ receptor agonists include dyskineticdisorders such as Parkinson's disease, neuroleptic-induced parkinsonismand tardive dyskinesias; depression; anxiety, memory disorders, sexualdysfunction and drug (eg. cocaine) dependency.

In a further aspect therefore the present invention provides a method oftreating conditions which require modulation of dopamine D₃ receptors,for example psychoses such as schizophrenia, which comprisesadministering to a subject in need thereof an effective amount of acompound of formula (I) or a physiologically acceptable salt thereof.

The invention also provides the use of a compound of formula (I) or aphysiologically acceptable salt thereof in the manufacture of amedicament for the treatment of conditions which require modulation ofdopamine D₃ receptors, for example psychoses such as schizophrenia.

A preferred use for D₃ antagonists according to the present invention isin the treatment of psychoses such as schizophrenia.

A preferred use for D₃ agonists according to the present invention is inthe treatment of dyskinetic disorders such as Parkinson's disease.

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect pharmaceuticalcompositions comprising a novel compound of formula (I) or aphysiologically acceptable salt thereof and a physiologically acceptablecarrier.

The compounds of formula (I) may be administered by any convenientmethod, for example by oral, parenteral, buccal, sublingual, nasal,rectal or transdermnal administration and the pharmaceuticalcompositions adapted accordingly.

The compounds of formula (I) and their physiologically acceptable saltswhich are active when given orally can be formulated as liquids orsolids, for example syrups, suspensions or emulsions, tablets, capsulesand lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or physiologically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or physiologically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstimtedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluoro-chlorohydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration arc conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a physiologicallyacceptable salt thereof calculated as the free base.

The physiologically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and 500 mg, preferably between 10mg and 400 mg, e.g. between 10 and 250 mg or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of thecompound of the formula (I) or a physiologically acceptable salt thereofcalculated as the free base, the compound being administered 1 to 4times per day. Suitably the compounds will be administered for a periodof continuous therapy, for example for a week or more.

Biological Test Methods

The ability of the compounds to bind selectively to human D₃ dopaminereceptors can be demonstrated by measuring their binding to clonedreceptors. The inhibition constants (K_(i)) of test compounds fordisplacement of [¹²⁵ I] iodosulpride binding to human D₃ dopaminereceptors expressed in CHO cells were determined as follows. The celllines were shown to be free from bacterial, fungal and mycoplasmalcontaminants, and stocks of each were stored frozen in liquid nitrogen.Cultures were grown as monolayers or in suspension in standard cellculture media. Cells were recovered by scraping (from monolayers) or bycentrifugation (from suspension cultures), and were washed two or threetimes by suspension in phosphate buffered saline followed by collectionby centrifugation. Cell pellets were stored frozen at -40° C. Crude cellmembranes were prepared by homogenisation followed by high-speedcentrifugation, and characterisation of cloned receptors achieved byradioligand binding.

Preparation of CHO Cell Membranes

Cell pellets were gently thawed at room temperature, and resuspended inabout 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37° C.), 20 mMEDTA, 0.2 M sucrose. The suspension was homogenised using anUltra-Turrax at full speed for 15 sec. The homogenate was centrifuged at18,000 r.p.m for 20 min at 4° C. in a Sorvall RC5C centrifuge. Themembrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @37° C.), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15min at 4° C. in a Sorvall RC5C. The membranes were washed two more timeswith icecold 50 mM Tris salts (pH 7.4 @ 37° C.). The final pellet wasresuspended in 50 mM Tris salts (pH 7.4 @ 37° C.), and the proteincontent determined using bovine serum albumin as a standard (Bradford,M. M. (1976) Anal. Biochem. 72, 248-254).

Binding Experiments on Cloned Dopamine Receptors

Crude ceil membranes were incubated with 0.1 nM [¹²⁵ I] iodosulpride(˜2000 Ci/mmol; Amersham, U.K.), and the test compound in a buffercontaining 50 mM Tris salts (pH 7.4 @ 37° C.), 120 mM NaCl, 5 mM KCl, 2mM CaCl₂, 1 mM MgCl₂, 0.1% (w/v) bovine serum albumin, in a total volumeof 1 ml for 30 min at 37° C. Following incubation, samples were filteredusing a Brandel Cell Harvester, and washed three times with ice-cold 50mM Tris salts (pH 7.4 @ 37° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mMMgCl₂. The radioactivity on the filters was measured using a Cobra gammacounter (Canberra Packard). Non-specific binding was defined as theradioligand binding remaining after incubation in the presence of 100 μMiodosulpride. For competition curves, 14 concentrations (half-logdilutions) of competing cold drug were used. Competition curves wereanalysed simultaneously whenever possible using non-linear least-squaresfitting procedures, capable of fitting one, two or three site models.

Compounds of Examples tested according to this method had pKi values inthe range 7.0 to 9.0 at the human dopamine D₃ receptor.

Functional Activity at Cloned Dopamine Receptors

The functional activity of compounds at human D2 and human D3 receptors(ie agonism or antagonism) may be determined using a CytosensorMicrophysiometer (McConnell HM et al Science 1992 257 1906-1912) InMicrophysiometer experiments, cells (hD2₋₋ CHO or hD3₋₋ CHO) were seededinto 12 mm Transwell inserts (Costar) at 300000 cells/cup in foetal calfserum (FCS)-containing medium. The cells were incubated for 6 h at 37°C. in 5% CO₂, before changing to FCS-free medium. After a further 16-18h, cups were loaded into the sensor chambers of the CytosensorMicrophysiometer (Molecular Devices) and the chambers perfused withrunning medium (bicarbonate-free Dulbecco's modified Eagles mediumcontaining 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min.Each pump cycle lasted 90s. The pump was on for the first 60s and theacidification rate determined between 68 and 88s, using the Cytosoftprogramme. Test compounds were diluted in running medium. In experimentsto determine agonist activity, cells were exposed (4.5 min for hD2, 7.5min for hD3) to increasing concentrations of putative agonist at halfhour intervals. Seven concentrations of the putative agonist were used.Peak acidification rate to each putative agonist concentration wasdetermined and concentration-response curves fitted using Robofit[Tilford, N. S., Bowen, W. P. μBaxter, G. S. Br. J. Pharmacol. (1995) inpress]. In experiments to determine antagonist potency, cells weretreated at 30 min intervals with five pulses of a submaximalconcentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells),before exposure to the lowest concentration of putative antagonist. Atthe end of the next 30 min interval, cells were pulsed again withquinpirole (in the continued presence of the antagonist) before exposureto the next highest antagonist concentration. In all, fiveconcentrations of antagonist were used in each experiment. Peakacidification rate to each agonist concentration was detemined andconcentration-inhibition curves fitted using Robofit.

Compounds of Examples 8(b) and 8(t) tested as antagonists according tothis method had pKb values in the range 8.3-9 at the human dopamine D₃receptor.

Pharmaceutical Formulations

The following represent typical pharmaceutical formulations according tothe present invention, which may be prepared using standard methods.

    ______________________________________                                        IV Infusion                                                                   Compound of formula (I)                                                                              1-40 mg                                                Buffer                 to pH ca 7                                             Solvent/complexing agent                                                                             to 100 ml                                              Bolus Injection                                                               Compound of formula (I)                                                                              1-40 mg                                                Buffer                 to pH ca 7                                             Co-Solvent             to 5 ml                                                ______________________________________                                    

Buffer: Suitable buffers include citrate, phosphate, sodiumhydroxide/hydrochloric acid.

Solvent: Typically water but may also include cyclodextfins (1-100 mg)and co-solvents such as propylene glycol, polyethylene glycol andalcohol.

    ______________________________________                                        Tablet                                                                        ______________________________________                                        Compound             1-40 mg                                                  Diluent/Filler*      50-250 mg                                                Binder               5-25 mg                                                  Disentegrant*        5-50 mg                                                  Lubricant            1-5 mg                                                   Cyclodextrin         1-100 mg                                                 ______________________________________                                         *may also include cyclodextrins                                          

Diluent: e.g. Microcrystalline cellulose, lactose, starch

Binder: e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose

Disintegrant: e.g. Sodium starch glycollate, crospovidone

Lubricant: e.g. Magnesium stearate, sodium stearyl funarate.

Oral Suspension

    ______________________________________                                        Oral Suspension                                                               ______________________________________                                        Compound             1-40 mg                                                  Suspending Agent     0.1-10 mg                                                Diluent              20-60 mg                                                 Preservative         0.01-1.0 mg                                              Buffer               to pH ca 5-8                                             Co-solvent           0-40 mg                                                  Flavour              0.01-1.0 mg                                              Colourant            0.001-0.1 mg                                             ______________________________________                                    

Suspending agent: e.g. Xanthan gum, microcrystalline cellulose

Diluent: e.g. sorbitol solution, typically water

Preservative: e.g. sodium benzoate

Buffer: e.g. citrate

Co-solvent: e.g. alcohol, propylene glycol, polyethylene glycol,cyclodextrin

The invention is further illustrated by the following non-limitingexamples:

DESCRIPTION 1 N-(4-Hydroxybutyl)-4-phenylbenzamide

To a stirred solution of 4-amino-1-butanol (7.34 g, 82 mmol) andtriethylamine (12.3 ml; 8.82 g, 87 mmol) in dichloromethane (100 ml) at0° C. was added a solution of 4-phenylbenzoyl chloride (18.36 g, 85mmol) in dichloromethane (800 ml) dropwise over 1.2 h. Resultant wasstirred at 0° C. for 2 h then at room temperature for 18 h. Theresulting white solid was filtered off (15.94 g) and the filtrate washedwith 5% aqueous sodium hydroxide (1L). The organic phase was dried (Na₂SO₄) and evaporated in vacuo to give a white solid (4.96 g) which wascombined with the above to give the title compound (20.9 g, 93%).

¹ H NMR (DMSO-d₆) δ: 1.4-1.7 (4H, m), 3.26 (2H, q, J=7 Hz), 3.42 (2H, q,J=7 Hz), 4.43 (1H, t, J=6 Hz), 7.35-7.55 (3H, m), 7.75 (4H, m), 7.94(2H, d, J=9 Hz), 8.52)1H, t, J=7 Hz)

DESCRIPTION 2 4-(4-Phenylbenzoylamino)butyraldehyde

To a mechanically-stirred solution ofN-(4-hydroxybutyl)-4-phenylbenzamide (11.2 g, 44.2 mmol) andtriethylamine (148 ml; 107.5 g, 1.06 mol) in dimethyl sulfoxide (250 ml)at room temperature was added, dropwise over 1 h, a solution ofpyridine-sulfur trioxide complex (43.7 g, 0.273 mol) in dimethylsulfoxide (200 ml) with external cooling using a cold water bath. Themixture was stirred at room temperature for 3 h, then 2M hydrochloricacid (550 ml) was added slowly with ice cooling. Resultant was dilutedwith water (1L) then extracted with ethyl acetate (3×500 ml). Thecombined extracts were washed with 2M hydrochloric acid (3×500 ml) andwater (3×500 ml) then dried (Na₂ SO₄) and evaporated in vacuo to give asemi solid (12 g). Chromatography on silica gel eluting with 10-100%ethyl acetate-hexane gave the title compound as a white solid (4.72 g,42%).

¹ H NMR (CDCl₃) δ: 2.00 (2H, m), 2.65 (2H, m), 3.52 (2H, q, J=8 Hz),6.54 (1H, br m), 7.35-7.53 (3H, m), 7.54-7.71 (4H, m), 7.85 (2H, m),9.83 (1H, s)

DESCRIPTION 3 4-Phthalimidobutyraldehyde Diethyl Acetal

A solution of 4-aminobutyraldehyde diethyl acetal (48.5 g, 0.3 mol) intetrahydrofuran (60 ml) was added dropwise to a stirred slurry ofN-(ethoxycarbonyl) phthalimide (65.93 g, 0.3 mol) in tetrahydrofuran(250 ml) at 0° C. After stirring at 0° C. for 0.16 h and at roomtemperature for 18 h the solvent was removed in vacuo and the residuedistilled at 1 mmHg to remove the ethyl carbamate by-product. Theresidual brown oil was allowed to cool to afford the title compound (91g, 93%).

Mass spectrum (API⁺): 218 (MH⁺ for aldehyde).

¹ H NMR (CDCl₃) δ: 1.20 (6H, t, J=7 Hz), 1.70 (4H, m), 3.35-3.85 (6H,m), 4.55 (1H, t, J=5 Hz), 7.70 (2H, m), 7.85 (2H, m).

DESCRIPTION 4 4-Phthalimidobutyraldehyde

A solution of 4-phthalimidobutyraldehyde diethyl acetal (125 g, 0.43mol) in a 1:1 mixture of tetrahydrofuran and 2N hydrochloric acid (800ml) was heated at reflux for 0.75 h. The mixture was cooled,concentrated to 400 ml and extracted into dichloromethane (3×200 ml).Combined organics were dried (Na₂ SO₄) and evaporated in vacuo to affordthe title compound as a brown oil that solidified on standing (95 g,100%).

Mass spectrum API⁺): 218 (MH⁺), C₁₂ H₁₁ NO₃ requires 217.

¹ H NMR (CDCl₃) δ: 2.00 (2H, m), 2.55 (2H, t, J=5 Hz), 3.75 (2H, t, J=5Hz), 7.70 (2H, m), 7.85 (2H, m), 9.30 (1H, s).

DESCRIPTION 57-Methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline

Prepared from 4-phthalimidobutyraldehyde (15.96 g, 0.074 mol) and7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g, 0.061 mol) using aprocedure similar to that of Example 1 (13.5 g, 60%).

Mass spectrum (API⁺): 365 (MH⁺) C₂₂ H₂₄ N₂ O₃ requires 364.

¹ H NMR (CDCl₃) δ: 1.70 (4H, m), 2.50 (2H, m), 2.70 (2H, m), 2.80 (2H,m), 3.55 (2H, s), 3.55-3.80 (5H, m), 6.55 (1H, d, J=2 Hz), 6.70 (1H, dd,J=2 Hz, 8 Hz, 7.00 (1H, d, J=8 Hz), 7.70 (2H, m), 7.85 (2H, m).

DESCRIPTION 6 2-(4-Aminobutyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

A solution of7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (17.4 g0.0478 mol) and hydrazine monohydrate (4.6 ml, 0.095 mol) in ethanol(300 ml) were stirred at room temperature for 18 h and at reflux for 1h. The cooled reaction mixture was filtered and the filtrate evaporatedin vacuo. The residue was dissolved in 2.5N hydrochloric acid, filteredthrough Kieselguhr and the filtrate basified with 0.880 ammonia. Theproduct was extracted into dichloromethanc (4×200 ml), the combinedextracts were dried (Na₂ SO₄) and evaporated in vacuo to afford thetitle compound as a brown oil (7 g, 63%).

Mass spectrum (API⁺): 235 (MH⁺) C₁₄ H₂₂ N₂ O requires 234.

¹ H NMR (CDCl₃) δ: 1.30-1.90 (4H, m), 2.50 (2H, m), 2.60-2.90 (8H, m),3.60 (2H, s), 3.75 (3H, s), 6.55 (1H, d, J=2 Hz), 6.70 (1H, dd, J=2 Hz,8 Hz), 7.00 (1H, d, J=8 Hz).

DESCRIPTION 77-Hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline

Prepared from7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (1.45 g,3.98 mmol) using a procedure similar to that of Example 2 (1.31 g, 94%).

Mass spectrum (API⁺): 351 (MH⁺) C₂₁ H₂₂ N₂ O₃ requires 350.

¹ H NMR (CDCl₃) δ: 1.70 (4H, m), 2.25-2.85 (1H, br s), 2.50 (2H, t, J=7Hz), 2.70 (2H, d, J=4 Hz), 2.85 (2H, d, J=4 Hz). 3.50 (2H, s), 3.75 (2H,t, J=7 Hz), 6.45 (1H, d, J=2 Hz), 6.60 (1H, dd, J=2 Hz, 8 Hz), 6.90 (1H,d, J=8 Hz), 7.70 (2H, m), 7.85 (2H, m).

DESCRIPTION 82-(4-Phthalimidobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Trifluoromethanesulfonic anhydride (0.53 ml, 3.14 mmol) was addeddropwise with stirring to an ice-cooled solution of7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (1 g,2.86 mmol) in anhydrous pyridine (10 ml). After stirring at roomtemperature for 18 h the reaction mixture was added to 10% aqueousCopper (II) sulfate (100 ml) and extracted into ethyl acetate (200 ml).The organic layer was separated, washed with 10% aqueous copper (II)sulfate (2×50 ml), dried (Na₂ SO₄) and evaporated in vacuo.Chromatography on silica gel using 10-100% ethyl acetate-hexane gradientelution gave the title compound as a green oil (0.45 g, 33%).

Mass spectrum (API⁺): 483 (MH⁺). C₂₂ H₂₁ F₃ N₂ O₅ S requires 482.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.55 (2H, t, J=7 Hz), 2.75 (2H, t, J=6Hz), 2.90 (2H, t, J=6 Hz), 3.60 (2H, s), 3.75 (2H, t, J=7 Hz), 6.90 (1H,d, J=2 Hz), 7.05 (1H, dd, J=2 Hz, 9 Hz), 7.15 (1H, d, J=9 Hz), 7.70 (2H,m), 7.85 (2H, m).

DESCRIPTION 92-(4-Aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinolin

Prepared from2-(4-phthalimidobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline(0.44 g, 0.91 mmol) using a procedure similar to that of Description 6(0.26 g, 81%).

Mass spectrum (API⁺): 353 (MH⁺). C₁₄ H₁₉ F₃ N₂ O₃ S requires 352.

¹ H NMR (CDCl₃) δ: 1.50 (6H, m), 2.50 (2H, t, J=7 Hz), 2.75 (4H, m),2.90 (2H, t, J=6 Hz), 3.60 (2H, s), 6.90 (1H, d, J=2 Hz), 7.0 (1H, dd,J=2 Hz, 9 Hz), 7.15 (1H, d, J=9 Hz).

DESCRIPTION 10 4-Bromobenzamidoxime

To a stirred solution of ice cooled methanol (115 ml), under argon, wasadded potassium tert-butoxide (10.12 g. 0.09 mol), portionwise. Afterstirring for 5 minutes hydroxylamine hydrochloride (6.71 g, 0.097 mol)was added in one portion. After stirring for 1 hour at room temperaturea slurry of 4-bromobenzonitrile, (10.88 g, 0.06 mol) in methanol (150ml) was added. The mixture was then heated at reflux for 4 hours, cooledand filtered. The filtrate was evaporated in vacuo to give the titlecompound as a colourless solid (14.12 g, quant.)

Mass spectrum (API⁺): Found 215 and 217 (MH⁺). C₇ H₇ BrN₂ O requires 214and 216.

DESCRIPTION 11 3-(4-Bromophenyl)-5-methyl-1,2,4-oxadiazole

4-Bromobenzamidoxime (13.05 g, 0.061 mol) was heated at reflux in aceticanhydride (60 ml) for 3 hours. The mixture was cooled and poured intoice-water (200 ml) and extracted into dichloromethane (2×200 ml). Theorganic layer was washed with water (100 ml), dried (Na₂ SO₄), andevaporated. The residue was partitioned between ether (200 ml) and water(200 ml). The ether layer was dried (Na₂ SO₄) and evaporated in vacuo togive a yellow solid (13.89 g) which was chromatographed on silica geleluting with 10-20% ethyl acetate/hexane to give the title compound as acolourless solid (8.94 g, 0.037 mol, 61%).

Mass spectrum (API⁺): Found 239 and 241 (MH⁺). C₉ H₇ BrN₂ O requires 238and 240.

DESCRIPTION 12 4-(4-(3-(5-Methyl-1,2,4-oxadazolyl))phenyl)Benzoic Acid

A mixture of 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (4.35 g, 0.018mol), 4-carboxybenzeneboronic acid (3 g, 0.018 mol), palladiumtetralistriphenylphosphine (0) (270 mg, 0.23 mmol), sodium carbonate(6.8 g, 0.064 mol) in a 1:1 mix of 1,2-dimethoxyethane and water (260ml), was heated at reflux, under argon, for 16 hours. The mixture wascooled and treated with ether (150 ml), and the aqueous phase separatedand acidified to pH5 with 5N HCl. The precipitated solid was filteredand dried to give the title compound as a beige solid (1.17 g, 4.18mmol, 23%).

Mass spectrum (API⁺): Found 279 (M-H)⁻. C₁₆ H₁₂ N₂ O₃ requires 280.

The following compounds were prepared in a manner similar to Description12

(a) 4-(4-(1-(2-Oxo)pyrrolidinyl)phenyl)benzoic acid

Mass spectrum (API⁺): Found 280 (M-H)⁻. C₁₇ H₁₅ NO₃ requires 281.

(b) 4-(3-Acetylphenyl)benzoic acid

¹ H NMR (DMSO) δ: 2.70 (3H, s), 3.00-4.50 (1H, br s), 7.70 (1H, t, J=8Hz), 7.90 (2H, d, J=8 Hz), 8.05 (2H, dd, J=8 Hz, 2 Hz), 8.10 (2H, d, J=8Hz), 8.25 (1H, s).

(c) 4-(4-(1-Methyl)pyrazolyl)benzoic add

Mass spectrum API⁺): Found 203 (MH⁺). C₁₁ H₁₀ N₂ O₂ requires 202.

(d) 4-(5-(1-Oxo)indanyl)benzoic acid

Mass spectrum API⁺): Found 251 (M-H)⁻. C₁₆ H₁₂ O₃ requires 252.

(e) 4-(3-(6-Methyl)pyridyl)benzoic acid

Mass spectrum (API⁺): Found 214 (MH⁺). C₁₃ H₁₁ NO₂ requires 213.

(f) 4-(2-Pyrimidyl)benzoic acid

¹ H NMR (DMSO) δ: 7.52 (1H, t, J=5 Hz), 8.08 (2H, d, J=11 Hz), 8.50 (2H,d, J=11 Hz), 8.97 (2H, d, J=5 Hz).

(g) 4-(4-Aminosulfonyl)phenylbenzoic acid

¹ H NMR (DMSO) δ: 7.48 (2H, s), 7.88 (2H, d, J=10 Hz), 7.95 (4H, s),8.08 (2H, d, J=10 Hz), 13.15 (1H, br s).

(h) 4-(3-Methylsulfonyl)phenylbenzoic acid

¹ H NMR (CDCl₃) δ: 3.30 (3H, s), 7.80 (1H, t, J=7 Hz), 7.95 (3H, m),8.10 (3H, m), 8.25 (1H, s), 13.10 (1H, br s).

(i) 4-(4-(2-(5-Methyl-1,3,4-oxadiazolyl))phenyl)benzoic acid

Mass spectrum (API⁺): Found 279 (M-H)⁻. C₁₆ H₁₂ N₂ O₃ requires 280.

¹ H NMR (DMSO) δ: 2.62 (3H, s), 7.93 (3H, m), 8.06 (5H, m)

(j)4-(3-Aminocarbonyl)phenylbenzoic acid

Mass spectrum (API⁺): Found 240 (M-H)⁻. C₁₄ H₁₁ NO₃ requires 241.

(k) 4-(3-Thienyl)benzoic acid

¹ H NMR (DMSO) δ: 7.60-7.70 (2H, m), 7.85 (2H, d, J=10 Hz), 7.98 (2H, d,J=10 Hz), 8.03-8.10 (1H, m), 13.00 (1H, br s).

(l) 4-(4Pyridyl)benzoic acid

Mass spectrum (API⁺): Found 198 (M-H)⁻. C₁₂ H₉ NO₂ requires 199.

DESCRIPTION 13 1-(4-Bromophenyl)-2-pyrrolidinone

To a solution of 4-bromoaniline (10 g, 58 mmol) in dry THF (150 ml),under argon was added triethylamine (6 g, 59 mmol) and 4-chlorobutyrylchloride (8.2 g 58 mmol) at 5° C. The mixture was stirred at 5° C. for40 mins and potassium tert-butoxide (16 g, 142 mmol) added in oneportion. After 10 mins the mixture was warmed to 25° C. and stirred for4 hours, then left to stand overnight. Water (10 ml) was added and themixture stirred for 30 mins. The mixture was diluted with ethyl acetate(200 ml) and 3% Na2CO₃ (aq) (120 ml). The aqueous layer was reextractedwith ethyl acetate (100 ml) and the combined extracts dried over Na₂SO₄. The solvent was evaporated in vacuo to give a brown solid (12 g).Chromatography on silica gel (˜200 g) using 30-60% ethyl acetate/hexanegradient elution gave the tide compound as a yellow crystalline solid(10.24 g, 74%).

Mass spectrum (API⁺): Found 240 and 242 (MH⁺). C₁₀ H₁₀ BrNO requires 239and 241.

DESCRIPTION 14 2-(4-Bromophenyl)-5-methyl-1,3,4-oxadiazole

A stirred suspension of 4-bromobenzoic hydrazide (4.0 g, 18.6 mmol) intriethyl orthoacetate (15 ml) was heated under reflux for 24 h. Thereaction mixture was cooled and the precipitate filtered, washed with60-80° C. petroleum ether (20 ml) and dried to give the title compoundas a yellow solid (3.86 g, 87%).

Mass spectrum (API⁺): Found 239 and 241 (MH⁺). C₉ H₇ BrN₂ O requires 238and 240.

¹ H NMR (CDCl₃) δ: 2.62 (3H, s), 7.64 (2H, m), 7.90 (2H, m).

DESCRIPTION 15 (4-Trifluoroacetamido)Butyraldehyde

To a solution of 4-aminobutyraldehyde diethyl acetal (16.10 g, 0.10mmol) and triethylamine (18.06 ml, 0.12 mol) in dichlorornethane (150ml) at 0° C. was added a solution of trifluoroacetic anhydride (16.9 ml,0.11 mol) in dichloromethane (60 ml). The reaction mixture was warmed toroom temperature and stirred for 3 h, then partitioned between 5% aqNaHCO₃ (400 ml) and dichloromethane (400 ml). The aqueous layer wasextracted further with dichloromethane (3×100 ml), the combined extractswere dried (Na₂ SO₄) and evaporated in vacuo to afford a pale yellow oilwhich was added to a stirred mixture of TBF (300 ml) and water (500 ml).5N Sulfuric acid (2.27 ml) was added and the reaction mixture left tostir at room temperature for 18 h. Saturated aqueous sodium bicarbonate(500 ml) was added and the product was extracted into dichloromcthane(4×100 ml). The combined organic extracts were dried (Na₂ SO₄) andevaporated in vacuo to afford the title compound as a yellow oil (15.42g, 65%).

¹ H NMR (CDCl₃) δ: 1.95 (2H, m), 2.62 (2H, t, J=8 Hz), 3.38 (2H, m),7.54-7.80 (1H, br s), 9.77 (1H, s).

DESCRIPTION 16 (4-Trifluoromethoxy)Phenylethylamine Hydrochloride

To a stirred solution of zirconium (IV) chloride (58.8 g, 250 mmol) indry tetrahydrofuran (750 ml) at 20° C. under argon was added,portionwise, sodium borohydride (37.6, 1.0 mol). Mixture was stirred for1 h, then 4-trifluoromethoxyphenylacetonitrile (20.0 g, 100 mmol) wasadded. Stirring was continued for 24 h, then water (310 ml) was addeddropwise, keeping the internal temperature below 10° C. The mixture waspartitioned between dilute aqueous ammonia (200 ml) and ethyl acetate(3×300 ml). Organic extracts were dried (Na₂ SO₄) and evaporated invacuo to give an oil which was treated with ethereal HCl to give thetitle compound (13.53 g. 57%).

Mass spectrum (API⁺): Found 206 (MH⁺). C₉ H₁₀ F₃ NO requires 205.

The following compound was prepared in a similar manner go description16.

(a) (4-Trifluoromethyl)phenethylamine hydrochloride

Mass spectrum (API⁺): Found 190 (MH⁺). C₉ H₁₀ F₃ N requires 189.

DESCRIPTION 17 N-(2-(4-Trifluoromethoxyphenyl)ethyl)Trifluoroacetamide

To a stirred mixture of (4-trifluoromethoxy)phenethylamine hydrochloride(13.53 g, 56 mmol) and 2,6-lutidine (13.1 ml; 12.05 g, 113 mmol) indichloromethane (200 ml) at 0° C. under argon was added, dropwise,trifluoroacetic anhydride (8.1 ml, 12.04 g, 57.4 mmol). Resultant wasstirred at 20° C. for 18 h then partitioned between water (200 ml) anddichloromethane (2×200 ml). Organic phase was washed with 1Mhydrochloric acid (150 ml), saturated aqueous NaHCO₃ (100 ml), dried(Na₂ SO₄) then evaporated in vacuo to give the title compound (13.94 g,81%) as a solid.

Mass spectrum (API⁻): Found 300 (M-H)⁻. C₁₁ H₉ F₆ NO₂ requires 301.

The following compound was prepared in a similar manner to description17.

(a) N-(2-(4-Trifluoromethylphenyl)ethyl)trifluoroacetamide

Mass spectrum (API⁻): Found 284 (M-H)⁻. C₁₁ H₉ F₆ NO requires 285.

DESCRIPTION 18 7-Trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline

N-(2-(4-Trifluoromethoxyphenyl)ethyl)trifluoroacetamide (13.94 g, 46.3mmol) was treated in a manner similar to that described in G. E.Stokker, Tetrahedron Letters 37 5453 1996. The resulting product (13.8g) was treated with anhydrous potassium carbonate (32.0 g, 0.232 mol) inmethanol (400 ml) containing water (40 ml) at reflux for 2 h. Themixture was cooled, evaporated in vacuo, then partitioned between water(400 ml) and dichloromethane (2×200 ml). Combined organic extracts weredried (Na₂ SO₄) and evaporated in vacuo to give the tide compound (9.05g, 95%) as an oil.

Mass spectrum (API⁺): Found 218 (MH⁺). C₁₀ H₁₀ F₃ NO requires 217.

The following compound was prepared in a similar manner to description18.

(a) 7-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 202 (MH⁺). C₁₀ H₁₀ F₃ N requires 201.

DESCRIPTION 192-(4-Trifluoroacetamido)butyl-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline

A mixture of 7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline (8.54 g,39.4 mmol), (4-Trifluoroacetamido)butyraldehyde (7.20 g, 39.4 mmol), andsodium triacetoxyborohydride (12.53 g, 59.1 mmol) in dichloroethane (400ml) was stirred at 20° C. for 18 h. Resultant was partitioned betweensaturated aqueous NaHCO₃ (700 ml) and dichloromethane (2×200 ml).Combined organic extracts were dried (Na₂ SO₄) and evaporated in vacuoto give an oil (13.4 g). Chromatography on silica eluting with 10-70%ethyl acetate-hexane gave the title compound (8.69 g, 57%) as an oil.

Mass spectrum (API⁻): Found 383 (M-H)⁻. C₁₆ H₁₈ F₆ N₂ O₂ requires 384.

The following compound was prepared in a similar manner to description19

(a)2-(4-Trifluoroacetamido)butyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 369 (MH⁺). C₁₆ H₁₈ F₆ N₂ O requires 368.

DESCRIPTION 202-(4-Aminobutyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline

A mixture of2-(4-Trifluoroacetamido)butyl-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline(8.68 g, 22.6 mmol), anhydrous potassium carbonate (16.0 g, 116 mmol),water (25 ml) and methanol (250 ml) was heated at reflux for 1 h,cooled, then evaporated in vacuo. Residue was partitioned between water(100 ml) and dichloromethane (3×100 ml) and the combined extracts weredried (Na₂ SO₄) then evaporated in vacuo to give the title compound(5.75 g, 88%) as an oil.

Mass spectrum (API⁺): Found 289 (MH⁺). C₁₄ H₁₉ F₃ N₂ O requires 288.

The following compound was prepared using a method similar todescription 20.

(a) 2-(4-Aminobutyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 273 (MH⁺). C₁₄ H₁₉ F₃ N₂ requires 272.

EXAMPLE 17-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline.

Sodium triacetoxyborohydride (4.66 g, 22 mmol) was added to a stirredmixture of 4-(4-phenylbenzoylamino)butyraldehyde (3.92 g, 15 mmol) and7-methoxy-1,2,3,4-tetrahydroisoquinoline [Daniel J. Sall et al., J. Med.Chem., 1987, 30, 2208] (2.40 g, 14.7 mmol) in 1,2-dichloroethane (200ml) at room temperature. After stirring for 16 h, dichloromethane (100ml) was added and the mixture was then washed with saturated aqueous K₂CO₃ (2×100 ml) and brine (100 ml). Drying (Na₂ SO ₄) and evaporation invacuo afforded a viscous oil which was chromatographed on silica gel,eluting with ethyl acetate, to give the title compound as a pale pinksolid (5.04 g, 83%).

Mass spectrum (API⁺): 415 (MH⁺)

¹ H NMR (CDCl₃) δ: 1.77 (4H, m), 2.56 (2H, m), 2.72 (2H, m), 2.81 (2H,m), 3.54 (4H, m), 3.68 (3H, s), 6.51 (1H, d, J=3 Hz), 6.72 (1H, dd, J=3and 8 Hz), 7.02 (1H, d, J=8 Hz), 7.26-7.74 (9H, bm), 7.76 (1H, bt, J=5Hz).

EXAMPLE 27-Hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline.

A solution of borontribromide i n dichloromethane (72 ml, 1M solution,72 mmol) was added dropwise with stirring to an ice-cooled solution of7-methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(5.00 g, 12.1 mmol) in dichloromethane (150 ml). After stirring at roomtemperature for 16 h the reaction mixture was poured onto a mixture ofcrushed-ice (200 g) and 0.880 aqueous ammonia (400 ml). The resultingmixture was extracted with dichloromethane (3×200 ml). The combinedorganics were washed with brine (200 ml) then dried (Na₂ SO₄) and thesolvent evaporated in vacuo to give the title compound as a pale yellowsolid (3.60 g, 75%).

Mass spectrum API⁺): 401 (MH⁺)

¹ H NMR (CDCl₃) δ: 1.52 (4H, m), 2.40-2.90 (6H, bm). 3.45 (4H , m), 6.47(1H, d, J=3 Hz), 6.64 (1H, dd, J=3 and 8 Hz), 6.86 (1H, d, J=8 Hz),7.28-7.85 (10H, bm).

The following compounds were prepared in a similar manner to Example 2

(a)2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): 426 (MH⁺). C₂₇ H₂₇ N₃ O₂ requires 425.

¹ H NMR (CDCl₃) δ: 1.75 (4H, br m), 2.55 (2H, br m), 2.75 (4H, m), 3.45(2H, s), 3.55 (2H m),6.35(1H, d, J=2 Hz), 6.65(1H, dd, J=2 Hz, 8 Hz),6.90 (1H d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 7.70 (7H, m), 7.85 (1H, t,J=5 Hz).

(b)2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺): 443 (MH⁺) C₂₈ H₃₀ N₂ O₃ requires 442.

¹ H NMR (CDCl₃) δ: 1.70 (4H, br m), 2.50 (2H, br m), 2.55 (3H, s), 2.75(4H, br m), 3.40 (2H, s), 3.50 (2H, m), 6.35 (1H, d, J=2 Hz), 6.65 (1H,dd, J=2 Hz, 8 Hz), 6.85 (1H, d, J=8 Hz), 7.40 (2H, d, J=8 Hz), 7.70 (6H,m), 8.00 (2H, d, J=8 Hz).

EXAMPLE 3 N-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy1,2,3,4-tetrahydroisoquinoline, Hydrochloride.

Trifluoromethanesulfonic anhydride (0.24 ml, 1.4 mmol) was addeddropwise with stirring to an ice-cooled solution of7-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(0.50 g, 1.3 mmol) in dry pyridine (8.0 ml). After stirring at roomtemperature for 16 h the reaction mixture was diluted with ethyl acetate(100 ml) and was then washed with a saturated aqueous solution of Copper(II) sulfate (6×50 ml) and brine (50 ml). Drying (Na₂ SO4) andevaporation of the solvent in vacuo afforded an orange oil which waschromatographed on silica gel, eluting with ethyl acetate, to give ayellow solid (0.19 g, 27%). Treatment with HCl-ether gave the titlecompound as a yellow powder.

Mass spectrum (API⁺): 533 (MH⁺)

¹ H NMR (CDCl₃) δ: 1.75 (4H, bm), 2.57 (2H, m), 2.75 (2H, m), 2.88 (2H,m), 3.52 (2H, m), 3.64 (2H, s), 6.95-7.15 (4H, m), 7.30-7.80 (9H, m).(Free base).

EXAMPLE 47-Methylsulfonyloxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline,Hydrochloride.

Methanesulfonyl chloride (0.26 ml, 3.3 mmol) was added dropwise withstaining to an ice-cooled solution of7-hydroxy-N-(4-(4phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(0.50 g, 1.3 mmol) and triethylamine (0.23 ml, 1.6 mmol) indichloromethane (20 ml). After stirring at room temperature for 16 h thereaction mixture was washed with saturated aqueous K₂ CO₃ (2×10 ml) andbrine (10 ml). Drying (Na2SO₄) and evaporation of the solvent in vacuoafforded a yellow solid which was chromatographed on silica, elutingwith 10% methanol in ethyl acetate, to give a pale yellow solid (0.24 g,39%). Treatment with HCl-ether gave the title compound as a pale yellowpowder.

Mass Spectrum (API⁺): 479 (MH⁺)

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.58 (2H, m), 2.75 (2H, m), 2.88 (2H,m), 3.05 (3H, s), 3.52 (2H, m), 3.62 (2H, s), 6.95 (1H, d, J=2 Hz), 7.08(3H, m), 7.30-7.54 (7H, bm), 7.75 (2H, d, J=10Hz) (Free base).

EXAMPLE 52-(4-(4-(3Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g,2.14 mmol) was added to a solution of2-(4-aminobutyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2.14mmol), 4-(3-cyanophenyl)benzoic acid (0.368 g, 2.14 mmol) and1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in dichloromethane (8 ml). Theresultant mixture was shaken for 18 h. before saturated aqueouspotassium carbonate (5 ml) was added and shaking continued 1 hr. Theorganic layer was chromatographed on silica gel using 10-100% ethylacetate-hexane gradient elution to afford the title compound as a yellowgum (0.57 g, 61%).

Mass spectrum (API⁺): 440 (MH⁺) C₂₈ H₂₉ N₃ O₂ requires 439.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, br m), 2.75 (2H, t, J=7 Hz),2.85 (2H, t, J=7 Hz), 3.50 (2H, m), 3.60 (2H, s), 3.75 (3H, s), 6.50(1H, d, J=2 Hz), 6.60 (1H, dd, J=2 Hz, 8 Hz), 7.00 (1H, d, J=8 Hz), 7.25(2H, d, J=9 Hz), 7.55 (1H, t, J=7 Hz), 7.65 (3H, m), 7.75 (2H, m), 8.10(1H, br m).

The following compounds were prepared in a similar manner to Example 5.

(a)2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): 440 (MH⁺). C₂₈ H₂₉ N₃ O₂ requires 439.

¹ H NMR (CDCl₃) δ: 1.80 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=7 Hz),2.85 (2H, t, J=7 Hz), 3.50 (2H, m), 3.55 (2H, s), 3.70 (3H, s), 6.5 (1H,d, J=2 Hz), 6.70 (1H, dd, J=2 Hz, 8 Hz), 7.05 (1H, d, J=8 Hz), 7.30 (2H,d, J=8 Hz), 7.65 (6H, m), 8.05 (1H, br m).

(b)2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): 457 (MH⁺). C₂₉ H₃₂ N₂ O₃ requires 456.

¹ H NMR (CDCl₃) δ: 1.80 (4H, m), 2.60 (2H, m), 2.65 (3H, s), 2.75 (2H,t, J=7 Hz), 2.85 (2H, t, J=7 Hz), 3.50 (2H, m), 3.60 (2H, s), 3.70 (3H,s), 6.50 (1H, d, J=2 Hz), 6.70 (1H, dd, J=2 Hz, 8 Hz), 7.00 (1H, d, J=8Hz), 7.35 (2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.65 (2H, d, J=8 Hz),7.95 (1H, br m), 8.05 (2H, d, J=8 Hz).

(c)7-Methoxy-2-(4-(4-(6-methyl)-3-pyridyl)benzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found: 430 (MH⁺). C₂₇ H₃₁ N₃ O₂ requires 429

¹ H NMR (CDCl₃) δ: 1.80 (4H, m), 2.55 (2H, m), 2.60 (3H, s), 2.75 (2H,t, J=6 Hz), 2.85 (2H, t, J=6 Hz), 3.50 (2H, m), 3.60 (2H, s), 3.70 (3H,s), 6.50 (1H, d, J=2 Hz), 6.70 (1H, dd, J=8 Hz, 2 Hz), 7.00 (1H, d, J=8Hz), 7.25 (1H, m), 7.30 (2H, d, J=8 Hz), 7.70 (2H, d, J=8 Hz), 7.75 (1H,m), 7.85 (1H, m), 8.70 (1H, m).

EXAMPLE 62-(4-(4-(3-Cyanophenyl)benzoylamino)butyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline(0.49 g, 1.14 mmol) in dichloromethane (3 ml) was treated with 1Nhydrogen chloride in diethyl ether (3 ml) and the mixture evaporated invacuo to afford the hydrochloride salt. The hydrochloride salt (054 g,1.14 mmol) in dichloromethane (40 ml) was ice cooled as a solution ofboron tribromide in dichloromethane (10 ml, 1M, 10 mmol) was addeddropwise. After stirring at room temperature for 18 h. the mixture wasadded to ice and 0.880 ammonia (100 ml) and the mixture stirred for 1 h.then extracted into dichloromethane (2×100 ml). Combined organicextracts were washed with brine (50 mL) dried (Na₂ SO₄) and evaporatedin vacuo to afford a beige solid (0.43 g, 89%).

Mass spectrum (API⁺): 426 (MH⁺). C₂₇ H₂₇ N₃ O₂ requires 425.

¹ H NMR (CDCl₃) δ: 1.75 (4H, br m), 2.55 (2H, br m), 2.80 (4H, m), 3.40(2H, s), 3.50 (2H, m), 6.35 (1H, d, J=2 Hz), 6.65 (1H, dd, J=2 Hz, 8Hz), 6.85 (1H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 7.55 (2H, t, J=8 Hz),7.65 (2H, d, J=8 Hz), 7.80 (4H, m).

EXAMPLE 72-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Trifluoromethanesulfonic anhydride (0.21 ml, 1.25 mmol) was addeddropwise with stirring to an ice cooled solution of2-(4-(4-(3-cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline(0.41 g, 0.96 mmol) in anhydrous pyridine (5 ml). After stirring at roomtemperature for 18 h. the mixture was poured into 10% aqueous copper(II) sulphate (100 ml). The mixture was extracted with ethyl acetate(2×50 ml) and the combined extracts washed with 10% aqueous copper (II)sulfate (2×50 ml). water (50 ml), dried (Na₂ SO₄) and evaporated invacuo. The residue was chromatographed on silica gel using 10-100% ethylacetate-hexane gradient elution to afford the title compound (0.263 g,49%).

Mass spectrum API⁺): 558 (MH⁺). C₂₈ H₂₆ F₃ N₃ O₄ S requires 557.

¹ H NMR (CDCl₃) δ: 1.75 (4H, br s), 2.60 (2H, m), 2.75 (2H, t, J=7 Hz),2.90 (2H, t, J=7 Hz), 3.50 (2H, m), 3.65 (1H, s), 6.90 (1H, d, J=2 Hz),7.00 (1H, dd, J=2 Hz, 8 Hz), 7.15 (3H, m), 7.45 (2H, d, J=8 Hz), 7.55(1H, t, J=8 Hz), 7.65 (1H, m), 7.75 (3H, m), 7.85 (1H, m).

The following compounds were prepared in a similar manner to Example 7.

(a)2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): 558 (MH⁺). C₂₈ H₂₆ F₃ N₃ O₄ S requires 557.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=7 Hz),2.90 (2H, t, J=7 Hz), 3.55 (2H, m), 3.65 (2H, s), 6.90 (1H, d, J=2 Hz),7.05 (1H, dd, J=2 Hz, 8 Hz), 7.15 (2H, m), 7.50 (2H, d, J=8 Hz), 7.65(2H, m), 7.75 (4H, m).

(b)2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺): 575 (MH⁺). C₂₉ H₂₉ F₃ N₂ O₅ S requires 574.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.65 (5H, m), 2.80 (2H, t, J=7 Hz),2.90 (2H, t, J=7 Hz), 3.55 (2H, m), 3.70 (2H, s), 6.90 (1H, d, J=2 Hz),7.05 (1H, dd, J=2 Hz, 8 Hz), 7.10 (1H, m), 7.18 (1H, d, J=8 Hz), 7.55(2H, d, J=8 Hz), 7.65 (2H, d, J=8 Hz), 7.75 (2H, d, J=8 Hz), 8.05 (2H,d, J=8 Hz).

EXAMPLE 82-(4-(4-(4-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Prepared from2-(4-aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline(0.15 g, 0.42 mmol) and 4-(4-methylsulfonylphenyl)benzoic acid (0.117 g,0.42 mmol) using a procedure similar to that of Example 5 (0.15 g, 74%).

Mass spectrum (API⁺): 611 (MH⁺). C₂₈ H₂₉ F₃ N₂ O₆ S₂ requires 610.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=7 Hz),2.90 (2H, t, J=7 Hz), 3.10 (3H, s), 3.50 (2H, m), 3.65 (2H, s), 6.90(1H,d, J=2 Hz), 7.00 (1H, dd, J=2 Hz, 8 Hz), 7.15 (1H, d, J=8 Hz), 7.20 (1H,m), 7.50 (2H, d, J=8 Hz), 7.75 (4H, m), 8.05 (2H, d, J=8 Hz).

The following compounds were prepared in a similar manner to Example 8

(a)2-(4-(4-(3-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺): Found MH⁺ 539. C₂₅ H₂₅ N₂ O₄ S₂ F₃ requires 538.

¹ H NMR (CDCl₃) δ: 1.72 (4H, m), 2.60 (2H, m), 2.70 (2H, m), 2.85, (2H,m), 3.50 (2H m), 3.63 (2H, s), 6.90-7.10 (3H, m), 7.12 (1H, d, J=8 Hz),7.30-7.65 (5H, m), 7.69 (2H, d, J=7 Hz).

(b)2-(4-(4-(3-Aminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found MH⁺ 576. C₂₈ H₂₈ F₃ N₃ O₅ S requires 575.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.72 (2H, m), 2.85 (2H,m), 3.52 (2H, m), 3.62 (2H, m), 5.80 (1H, m), 6.3 (1H, m), 6.90 (1H, d,J=2 Hz), 7.00-7.20 (3H, m), 7.40-7.65 (3H, m), 7.70-7.90 (4H, m), 8.05(1H, s)

(c)2-(4-(4-(3-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 575 (MH⁺). C₂₉ H₂₉ F₃ N₂ O₅ S requires 574.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.65 (3H, s), 2.75 (2H,t, J=6 Hz), 2.90 (2H, t, J=9 Hz), 3.55 (2H, m), 3.65 (2H, s), 6.90 (1H,d, J=2 Hz), 6.95-7.10 (2H, m), 7.15 (1H, d, J=8 Hz), 7.55 (3H, m), 7.75(3H, m), 7.95 (1H, dd, J=8 Hz, 2 Hz), 8.15 (1H, m).

(d)2-(4-(4-(3-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 611 (MH⁺). C₂₈ H₂₉ F₃ N₂ O₆ S₂ requires 610.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=6 Hz),2.90 (2H, t, J=6 Hz), 3.10 (3H, s), 3.55 (2H, m), 3.65 (2H, s), 6.90(1H, d, J=2 Hz), 7.05 (1H, dd, J=8 Hz, 2 Hz). 7.15 (1H, d, J=8 Hz), 7.20(1H, m), 7.50 (2H, d, J=8 Hz), 7.70 (1H, m), 7.75 (2H, d, J=8 Hz), 7.85(1 H, m), 7.95 (1H, m), 8.10 (1H, m).

(e)2-(4-(4-(1-Methyl-4-pyrazolyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺): Found 537 (MH⁺). C₂₅ H₂₇ F₃ N₄ O₄ S requires 536

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=6 Hz),2.90 (2H, t, J=6 Hz), 3.50 (2H, m), 3.65 (2H, s), 3.95 (3H, s), 6.90(1H, d, J=2 Hz), 7.05 (2H, m), 7.15 (1H, d, J=8 Hz), 7.35 (2H, d, J=8Hz), 7.62 (1H, s), 7.65 (2H, d, J=8 Hz), 7.75 (1H, s).

(f)2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazoIyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 539 (MH⁺). C₂₄ H₂₅ F₃ N₄ O₅ S requires 538.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.65 (2H, m), 2.70 (3H, s), 2.75 (2H,t, J=6 Hz), 2.90 (2H, t, J=6 Hz), 3.50 (2H, m), 3.60 (2H, s), 6.85 (1H,d, J=2 Hz), 7.00 (1H, dd, J=8 Hz, 2 Hz), 7.15 (1H, d, J=8 Hz), 7.25 (1H,m), 7.70 (2H, d, J=8 Hz), 7.95 (2H, d, J=8 Hz).

(g)2-(4-(4-(2-Pyrimidyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺): Found 535 (MH⁺). C₂₅ H₂₅ F₃ N₄ O₄ S requires 534.

¹ H NMR (CDCl₃) δ: 1.80 (4H, m), 2.60 (2H, m), 2.75 (2H, t, J=6 Hz),2.90 (2H, m, J=6 Hz), 3.55 (2H, m), 3.60 (2H, s), 6.95 (1H, d, J=2 Hz),7.00 (1H, dd, J=8 Hz), 7.15 (1H, m), 7.17 (1H, m), 7.25 (1H, m), 7.75(2H, d, J=8 Hz), 8.35 (2H, d, J=8 Hz), 8.85 (2H, d, J=5 Hz).

(h)2-(4-(4-(4-(1-(2-Oxo)pyrrolidinyl)phenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum API⁺). Found 616 (MH⁺). C₃₁ H₃₂ F₃ N₄ O₅ S requires 615.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.20 (2H, m), 2.60 (4H, m), 2.75 (2H,t, J=6 Hz), 2.85 (2H, t, J=6 Hz), 3.50 (2H, m), 3.65 (2H, s), 3.90 (2H,t, J=7 Hz), 6.90 (1H, d, J=2 Hz), 7.05 (2H, m), 7.15 (1H, d, J=8 Hz),7.50 (2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.75 (4H, m).

(i)2-(4-(4-(4-Arminosulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 612 (MH⁺). C₂₇ H₂₈ F₃ N₃ O₆ S₂ requires 611.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.80 (2H, m), 2.95 (2H,m), 3.50 (2H, m), 3.65 (2H, s), 4.10 (2H, br s), 6.95 (1H, br s), 7.05(1H, d, J=8 Hz), 7.20 (1H, d, J=8 Hz), 7.40 (1H, s), 7.60 (2H, d, J=8Hz), 7.70 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 8.00 (2H, d, J=8 Hz).

(j)2-(4-(4-(5-(1-Oxo)indanyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 587 (MH⁺). C₃₀ H₂₉ F₃ N₂ O₅ S requires 586.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.75 (4H, m), 2.85 (2H,t, J=7 Hz), 3.20 (2H, t, J=6 Hz), 3.55 (2H, m), 3.65 (2H, s), 6.90 (1H,d, J=2 Hz), 7.00 (1H, dd, J=8 Hz, 2 Hz), 7.15 (2H, m), 7.50 (2H, d, J=8Hz), 7.55 (1H, m), 7.65 (1H, s), 7.75 (2H, d, J=8 Hz), 7.80 (1H, d, J=8Hz).

(k)2-(4-(3-(6-(1-Pyrrolyl)pyridyl)carboxamido)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found MH⁺ 523. C₂₄ H₂₅ F₃ N₄ O₄ S requires 522.

¹ H NMR (CDCl₃) δ: 1.74 (5H, m), 2.58 (2H, m), 2.74 (2H, m), 2.85 (2H,m), 3.51 (2H, m), 3.64 (2H, s), 6.37 (2H, m), 6.96 (2H, m), 7.12 (2H,m), 7.50 (2H, m), 8.01 (1H, dd, J=8 Hz, 2 Hz), 8.65 (1H, d, J=2 Hz).

(l)2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazolyl)-phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 615 (MH⁺). C₃₀ H₂₉ F₃ N₄ O₅ S requires 614.

¹ H NMR (CDCl₃) δ: 1.76 (4H, m), 2.63 (2H, m), 2.68 (3H, s), 2.78 (2H,m), 2.90 (2H, m), 3.53 (2H, m), 3.67 (2H, s), 6.98 (3H, m), 7.15 (1H, d,J=7 Hz), 7.55 (2H, d, J=7 Hz), 7.68 (2H, d, J=7 Hz), 7.77 (2H, d, J=7Hz), 8.15 (2H, d, J=7 Hz).

(m)2-(4-(4-(2-(5-Methyl-1,3,4-oxadiazolyl)phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 615 (MH⁺). C₃₀ H₂₉ F₃ N₄ O₅ S requires 614.

¹ H NMR (CDCl₃) δ: 1.70-1.89 (4H, m), 2.61 (2H, t, J=5 Hz), 2.65 (3H,s), 2.75 (2H, t, J=5 Hz), 2.90 (2H, t, J=5 Hz), 3.52 (2H, m), 3.61 (2H,s), 6.91 (1H, d, J=4 Hz), 7.02 (1H, dd, J=4 and 10 Hz), 7.15 (2H, m),7.52 (2H, d, J=7 Hz), 7.70 (2H, d, J=7 Hz). 7.79 (2H, d, J=7 Hz), 8.10(2H, d, J=7 Hz).

(n)2-(4-(4-(3-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 590 (MH⁺). C₂₉ H₃₀ F₃ N₃ O₅ S requires 589.

¹ H NMR (CDCl₃) δ: 1.71-1.82 (4H, m), 2.59 (2H, t, J=5 Hz), 2.75 (2H, tJ=5 Hz 2.89 (2H, t, J=5 Hz), 3.06 (3H, d, J=6 Hz), 3.51 (2H, q, J=5 Hz),3.62 (2H, s), 6.75 (1H, m), 6.91 (1H, d, J=3 Hz), 7.00-7.10 (2H, m),7.12 (1H, d, J=5 Hz), 7.49-7.56 (3H, m), 7.67-7.79 (4H, m), 7.98-8.00(1H, m).

(o)2-(4-(4-(4-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 590 (MH⁺). C₂₉ H₃₀ F₃ N₃ O₅ S requires 589.

¹ H NMR (CDCl₃): 1.59-1.89 (4H, m), 2.60 (2H, t, J=4 Hz), 2.75, (2H, t,J=4 Hz), 2.88 (2H, t, J=4 Hz), 3.05 (3H, d, J=5 Hz), 3.45-3.60 (2H, m),3.65 (2H, br s), 5.05-5.25 (1H, br s), 6.19-6.30 (1H, m), 6.90-7.15 (3H,m), 7.50 (2H, d, J=7 Hz), 7.61 (2H, d, J=7 Hz), 7.75 (2H, d, J=7 Hz),7.85 (2H, d, J=7 Hz).

(p)2-(4-(4-(4-Pyridyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 534 (MH⁺). C₂₆ H₂₆ F₃ N₃ O₄ S requires 533.

¹ H NMR (CDCl₃) δ: 1.80 (4H, m), 2.60 (2H, m), 2.76 (2H, t, J=7 Hz),2.88 (2H, t, J=7 Hz), 3.54 (2H, m), 3.65 (2H, s), 6.92 (1H, d, J=3 Hz),7.02 (1H, dd, J=3,8 Hz), 7.15 (2H, m), 7.38-7.58 (4H, m), 7.78 (2H, d,J=10 Hz), 8.68 (2H, d, J=7 Hz).

(q)2-(4-(4-(2-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found: 539 (MH⁺). C₂₅ H₂₅ F₃ N₂ O₅ S₂ requires538.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.58 (2H, m), 2.72 (2H, t, J=7 Hz),2.85 (2H, t, J=7 Hz), 3.50 (2H, m), 3.60 (2H, s), 6.94 (1H, d, J=3 Hz),6.96-7.05 (4H, m), 7.34 (2H, m), 7.48 (2H, d, J=8 Hz), 7.66 (2H, d, J=8Hz).

(r)2-(4-(2-(5-(2-Pyridyl)thienylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 540 (MH⁺). C₂₄ H₂₄ F₃ N₃ O₄ S₂ requires 539.

¹ H NMR (CDCl₃) δ: 1.70 (4H, m), 2.58 (2H, m), 2.75 (2H, t, J=7 Hz),2.80 (2H, t, J=7 Hz), 3.47 (2H, m), 3.65 (2H, s), 6.84 (1H, t), 6.94(1H, d, J=3 Hz), 7.02 (1H, dd, J=3, 10 Hz), 7.08-7.25 (2H, m), 7.47 (2H,m), 7.58-7.78 (2H, m), 8.60 (1H, d, J=7 Hz).

(s)2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoroethoxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 511 (MH⁺). C₂₉ H₃₀ F₃ N₂ O₃ requires 510.

¹ H NMR (CDCl₃) δ: 1.78 (4H, m), 2.60 (2H, m), 2.65 (3H, s), 2.75 (2H,m), 2.87 (2H, m), 3.53 (2 H, m), 3.62 (2H, s), 6.87 (1H, br s), 6.99(1H, m), 7.09 (1H, d, J=8 Hz), 7.32 (1H, m), 7.46 (2H, d, J=8 Hz), 7.65(2H, d, J=8 Hz), 7.74 (2H, d, J=8 Hz), 8.04 (2H, d, J=8 Hz).

(t)2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 495 (MH⁺). C₂₉ H₂₉ F₃ N₂ O₂ requires 494.

¹ H NMR (CDCl₃) δ: 1.79 (4H, m), 2.62 (2 H, m), 2.65 (3H, s), 2.76 (2H,m), 2.93 (2H, m), 3.53 (2H, m), 3.68 (2H, s), 7.18 (1H, d, J=8 Hz), 7.27(1H, d, J=4 Hz), 7.36 (1H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz), 7.62 (2H,d, J=8 Hz), 7.88 (2H, d, J=8 Hz), 8.02 (1H, br s), 8.03 (2H, d, J=8 Hz).

EXAMPLE 92-(4-(4-Phenylbenzoylamino)butyl)-7-(2-thienyl)sulfonyloxy-1,2,4-tetrahydroisoquinoline

A solution of7-hydroxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,4-tetrahydroisoquinoline(0.5 g, 1.3 mmol), thiophene-2-sulfonyl chloride (0.27 g, 1.5 mmol) andtriethylamine (0.21 ml, 1.5 mmol) in dichloromethane (20 ml) was stirredat room temperature for 18 h. The reaction mixture was poured ontosaturated aqueous potassium carbonate (25 ml) and extracted intodichloromethane (3×20 ml). The combined extracts were washed with brine,dried (Na₂ SO₄) and evaporated in vacuo. Chromatography on silica using10-100% ethyl acetate-pentane gradient elution gave the title compoundas a yellow solid (226 mg, 32%).

Mass spectrum (API⁺): 547 (MH⁺). C₃₀ H₃₀ N₂ O₄ S₂ requires 546.

¹ H NMR (CDCl₃) δ: 1.71 (4H, m), 2.54 (2H, m), 2.69 (2H, m), 2.82 (2H,m), 3.30-3.60 (4H, m), 6.60-6.85 (2H, m), 6.90-7.17 (4H, m), 7.30-7.78(10H, m).

The following compound was prepared in a similar manner to Example 9.

(a)7-(4-(3,5-Dimethyl)isoxazolyl)sulfonyloxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): 560 (MH⁺). C₃₁ H₃₃ N₃ O₅ S requires 559.

¹ H NMR (CDCl₃) δ: 1.71 (4H, m), 2.32 (3H, s), 2.39 (3H, s), 2.54 (2H,m), 2.69 (2H, m), 2.84 (2H, m), 3.38-3.65 (4H, m), 6.65-6.85 (2H, m),6.95-7.20 (2H, m), 7.30-7.60 (7H, m), 7.75 (2H, d, J=8 Hz).

EXAMPLE 107-Acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

2-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline(0.515 g, 0.97 mmol), (1-ethoxyvinyl)tributyltin (0.420 g, 1.16 mmol),lithium chloride (0.121 g, 2.85 mmol) andtetrakis-(triphenylphosphine)palladium (0) (0.057 g, 0.05 mmol) in1,4-dioxane (15 ml) were heated at reflux under argon for 16 h. Thecooled reaction mixture was treated with water (2.0 ml) and aqueous 5Nhydrogen chloride (4 drops), then stirred at room temperature for 0.5 h.The resulting solution was poured onto saturated, aqueous potassiumcarbonate (20 ml) and the product was extracted with ethyl acetate (2×25ml). The combined organic extracts were washed with brine (40 ml), dried(Na₂ SO₄) and evaporated in vacuo. The residue was chromatographed onsilica using 50-100% ethyl acetate--pentane gradient elution to affordthe title compound as a colourless solid (0.210 g, 51%).

Mass spectrum (API⁺): 427 (MH⁺). C₂₈ H₃₀ N₂ O₂ requires 426.

¹ H NMR (CDCl₃) δ: 1.78 (4H, br m), 2.45 (3H, s), 2.61 (2H, m), 2.75(2H, t, J=8 Hz), 2.92 (2H, t, J=8 Hz), 3.52 (2H, m), 3.66 (2H, s), 7.15(2H, d, J=8 Hz), 7.30-7.50 (11H, br m).

EXAMPLE 112-(4-(4-Phenylbenzoylamino)butyl)-7-(3-pyridyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline

To a stored solution of7-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(05 g, 1.3 mmol) and triethylamine (0.21 ml; 1.5 mmol) indichloromethane (20 ml) was added pyridine-3-sulfonyl chloride (0.25 g,1.4 mmol). The mixture was stirred for 18 h, then partitioned betweendichloromethane (4×30 ml) and saturated aqueous NaHCO₃ (100 ml).Combined organic extracts were dried (Na₂ SO₄) and evaporated in vacuoto give an oil. Chromatography on silica using 0-5% methanolethylacetate gradient elution gave the title compound (0.06 g, 12%) as anoil.

¹ H NMR(CDCl₃) δ: 1.62-1.87 (4H, m), 2.55-2.70 (2H, m), 2.72-2.92 (4H,m), 3.41-3.60 (2H, m), 3.65 (2H, s), 6.68-6.78 (2H, m), 7.00 (1H, d,J=10 Hz), 7.20 (1H, t, J=4 Hz), 7.31-7.65 (8H, m), 7.78 (2H, d, J=10Hz), 8.05-8.15 (1H, m), 8.88 (1H, dd, J=2 and 4 Hz), 9.00 (1H, d, J=2Hz).

The following compounds were prepared in a similar manner to Example 11

(a)2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 566 (MH⁺). C₃₃ H₃₁ N₃ O₄ S requires 565.

¹ H NMR (CDCl₃) δ: 1.64-1.80 (4H, m), 2.53 (2H, t, J=5 Hz), 2.70 (2H, t,J=5 Hz), 2.82 (2H, t, J=5 Hz), 3.49-3.60 (4H, m), 6.89-6.92 (2H, m),7.00 (1H, d, J=6 Hz), 7.12 (1H, t, J=6 Hz), 7.32-7.60 (7H, m), 7.71-7.80(4H, m), 7.92 (1H, dd, 2 and 6 Hz), 8.03 (1H, dd, J=2 and 6 Hz).

(b)2-(4(4-(Phenylbenzoylamino)butyl)-7-(3cyanophenyl)sulfonyloxy-1,2,3,4-tetrhydroisoquinoline

Mass spectrum (API⁺) Found 566 (MH⁺) C₃₀ H₃₁ N₃ O₄ S requires 565.

¹ H NMR (CDCl₃) δ: 1.55-1.70 (4H, m), 2.55 (2H, t, J=6 Hz), 2.70 (2H, t,J=6 Hz), 2.85 (2H, t, J=6 Hz), 3.49-3.58 (4H, m), 6.62-6.72 (2H, m),7.00 (1H, d, J=7 Hz), 7.10 (1H, t, J=6 Hz), 7.35-7.80 (10H, m),7.89-8.10 (3H, m).

(c)2-(4(4-Phenylbenzoylamino)butyl)-7-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found: 547 (MH⁺) C₃₀ H₃₀ N₂ O₄ S₂ requires 546.

¹ H NMR (CDCl₃) δ: 1.61-1.87 (4H, m), 2.52 (2H, t, J=5 Hz), 2.70 (2H, t,J=5 Hz), 2.83 (2H, t, J=5 Hz), 3.42 -3.58 (4H, m), 6.70 (2H, m), 7.00(2H, d, J=6 Hz), 7.31-7.55 (8H, m), 7.57 (2H, d, J=6 Hz), 7.72 (1H, d,J=6 Hz), 7.90 (1H, m).

EXAMPLE 127-Methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

A mixture of thallium (III) nitrate trihydrate (0.73 g, 1.6 mmol), K10clay (1.65 g) and trimethyl orthoformate (1.8 ml, 1.6 mmol) in methanol(3 ml) was stirred at room temperature for 15 min. The solvent wasevaporated in vacuo and dichloromethane (5 ml) was added to the residue.To this mixture was added a solution of7-acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline,hydrochloride (0.50 g, 1.1 mmol) in dichloromethane (15 ml) and thereaction mixture was stirred for 4 h. The suspended solid was removed byfiltration and the filtrate was washed with saturated aqueous potassiumcarbonate (2×30 ml), then brine (30 ml). Drying (Na₂ SO₄) andevaporation in vacuo afforded a yellow gum which was chromatographed onsilica using 20-100% ethyl acetate--pentane gradient elution to affordthe title compound as an off-white solid (0.15 g, 30%).

Mass spectrum (API⁺): Found 457 (MH⁺). C₂₉ H₃₂ N₂ O₃ requires 456.

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.58 (2H, m), 2.74 (2H, t, J=7 Hz),2.86 (2H, t, J=7 Hz), 3.52 (4H, m), 3.60 (2H, s), 3.65 (3H, s), 6.90(1H, s), 7.04 (2H, s), 7.30-7.60 (8H, m), 7.72 (2H, d, J=8 Hz).

EXAMPLE 137-Ethoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

A stirred, ice-cooled solution of7-methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(0.202 g, 0.46 mmol) in ethanol (10 ml) was treated with concentratedsulfuric acid (0.53 ml, 0.53 mmol). The mixture was heated at reflux for2 h. The solvent was evaporated in vacuo and the residue was dissolvedin ethyl acetate (30 ml) and saturated aqueous sodium bicarbonatesolution (30 ml). The organic phase was separated and washed with brine.Drying (Na₂ SO₄) and evaporation in vacuo afforded an orange oil whichwas chromatographed on silica using 50-100% ethyl acetate-pentanegradient elution to afford the title compound as a colourless oil (120mg, 56%).

Mass spectrum (API⁺): Found 471 (MH⁺). C₃₀ H₃₄ N₂ O₃ requires 470.

¹ H NMR (CDCl₃) δ: 1.24 (3H, t, J=8 Hz), 1.75 (4H, m), 2.56 (2H, m),2.74 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 3.50 (4H, m), 3.62 (2H, s),4.10 (2H, q, J=8 Hz), 6.92 (1H, s), 7.05 (2H, s), 7.30-7.62 (8H, m),7.70 (2H, d, J=11 Hz).

EXAMPLE 147-(2-Cyanophenoxy)-2-(4-(4-phenylbenzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline

A stirred mixture of7-hydroxy-2-(4-(4phenylbenzoylamino)butyl)-1,2,3,4-tetrhydroisoquinoline(0.605 g, 1.51 mmol), 2-fluorobenzonitrile (0.182 g, 1.51 mmol) andpotassium carbonate (0.518 g, 3.75 mmol) in dimethylformamide (8 ml) washeated at 120° C. for 16 h. The cooled reaction mixture was partitionedbetween ethyl acetate (30 ml) and water (20 ml). The organic phase wasseparated and washed with water (4×20 ml) then brine (20 ml). Drying(Na₂ SO₄) and evaporation in vacuo afforded an oil which waschromatographed on silica using 20-100% ethyl acetate-pentane gradientelution. The title compound was afforded as a pale yellow oil (0.400 g,53%).

Mass spectrum (API⁺): Found 502 (MH⁺). C₃₃ H₃₁ N₃ O₂ requires 501.

¹ H NMR (CDCl₃) δ: 1.78 (4H, m), 2.56 (2H, m), 2.76 (2H, t, J=7 Hz),2.88 (2H, t, J=7 Hz), 3.52 (2H, m), 3.60 (2H, s), 6.75 (2H, m), 6.85(1H, dd, J=3, 8 Hz), 7.02 (3H, m), 7.30-7.68 (9H, m), 7.75 (2H, d, J=10Hz).

EXAMPLE 157-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

7-Bromo-2-tufluoroacetyl-1,2,3,4-tetrahydroisoquinoline (7.20 g, 23mmol) and potassium carbonate (16.8 g, 122 mmol) in 10% aqueous methanol(250 ml) were heated at reflux, with stirring, for 2 h. After coolingthe solvents were removed in vacuo and the residue was partitionedbetween water (200 ml) and dichloromethanc (100 ml). The aqueous layerwas extracted further with dichloromethane (2×50 ml). The combinedorganics were washed with brine, dried Na₂ SO₄) and evaporated in vacuoto afford 7-bromo1,2,3,4-tetrahydroisoquinoline as a brown oil (4.50 g,21 mmol, 92%). The oil was stirred with4-(4-phenylbenzoylaminobutyraidehyde (5.71 g, 21 mmol) indichloromethane (250 ml) and sodium triacetoxyborohydride (6.71 g, 32mmol) was added. After stirring for 16 h at room temperature the mixturewas diluted with dichloromethane (100 ml) then washed with brine (100ml). Drying (Na₂ SO₄) and evaporation of the solvent in vacuo gave asolid which was chromatographed on silica using 20-100% ethylacetate-pentane gradient elution to afford the title compound as a whitesolid (6.68 g, 68%).

Mass spectrum (API⁺): Found 463, 465 (MH⁺). C_(26H) ₂₇ BrN₂ O requires462, 464.

EXAMPLE 167-Cyano-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline

A mixture of7-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline(3.84 g, 8.3 mmol) and copper (I) cyanide (1.04 g, 11.4 mmol) inN-methyl-2-pyrrolidinone (20 ml) was heated at reflux for 1.5 h. Thecooled mixture was poured onto 0.880 ammonia (50 ml) and crushed ice(˜50 g) with stirring. The product was extracted into ethyl acetate (100ml) and washed further with 0.880 ammonia (2×30 ml), then brine. Drying(Na₂ SO₄) and evaporation of the solvent in vacuo afforded a brown oil.Chromatography on silica using 20-100% ethyl acetate-pentane gradientelution afforded the title compound as a colourless gum (1.58 g, 47%).

¹ H NMR (CDCl₃) δ: 1.75 (4H, m), 2.60 (2H, m), 2.74 (2H, t, J=7 Hz),2.92 (2H, t, J=7 Hz), 3.50 (2H, m), 3.62 (2H, s), 7.05 (1H, t), 7.16(1H, d, J=10 Hz), 7.26-7.52 (9H, m), 7.74 (2H, d, J=10 Hz).

We claim:
 1. A compound of formula (I): ##STR11## wherein: R¹ representsa substituent selected from: a hydrogen or halogen atom; a hydroxy,cyano, nitro, trifluoromethyl, trifluoromethoxy,trifluoromethanesulfonyloxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, arylC₁₋₄ alkoxy,C₁₋₄ alkylthio, C₁₋₄ alkoxyC₁₋₄ akyl, C₃₋₆ cycloalkylC₁₋₄ alkoxy, C₁₋₄alkanoyl, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylsulphonyl, C₁₋₄alkylsulphonyloxy, C₁₋₄ alkylsulphonylC₁₋₄ alkyl, arylsulphonyl,arylsulphonyloxy, arylsulphonylC₁₋₄ alkyl, C₁₋₄ alkylsulphonamido, C₁₋₄alkylamido, C₁₋₄ alkylsulphonamidoC₁₋₄ alkyl, C₁₋₄ alkyamidoC₁₋₄ alkyl,arylsulphonamido, arylcarboxamido, arylsulphonarnidoC₁₋₄ alkyl,arylcarboxamidoC₁₋₄ alkyl, aroyl, aroylC₁₋₄ alkyl, or arylC₁₋₄ alkanoylgroup; a group R³ OCO(CH₂)_(p), R³ CON(R⁴)(CH₂)_(p), R³ R⁴ NCO(CH₂)_(p)or R³ R⁴ NSO₂ (CH₂)_(p) where each of R³ and R⁴ independently representsa hydrogen atom or a C₁₋₄ alkyl group or R³ R⁴ forms part of a C₃₋₆azacyloalkane or C₃₋₆ (2-oxo)azacycloalkane ring and p represents zeroor an integer from 1 to 4; or a group Ar² --Z, wherein Ar² represents anoptionally substituted phenyl ring or an optionally substituted 5- or6-membered aromatic heterocyclic ring and Z represents a bond, O, S, orCH₂ ;R² represents a hydrogen atom or a C₁₋₄ alkyl group; q is 1 or 2;Ar and Ar¹ each independently represent an optionally substituted phenylring or an optionally substituted 5- or 6-membered aromatic heterocyclicring; and Y represents a bond, --NHCO--, --CONH--, --CH₂ --, or--(CH₂)_(m) Y¹ (CH₂)_(n) --, wherein Y¹ represents O, S, SO₂, or CO andm and n each represent zero or 1 such that the sum of m+n is zero or 1;or a salt thereof.
 2. A compound according to claim 1 wherein qrepresents
 1. 3. A compound as claimed in claim 1 wherein Y represents abond.
 4. A compound as claimed in claim 1 wherein Ar representsunsubstituted phenyl.
 5. A compound of formula (I) whichis:7-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-Hydroxy-N-4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinolineN-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methylsulfonyloxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquimoline;2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-terrahydroisoquinoline;2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethydsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;7-(4-(3,5-Dimethyl)isoxazolyl)sulfonyloxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-Acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-(4-(6-methyl)-3-pyridyl)benzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-Aminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydoisoquinoline;2-(4-(4-(3-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(1-Methyl-4-pyrazolyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4(-(5-Methyl-1,2,4-oxadiazolyl)benzoylamino)butyl)-7-triuoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(2-Pyrimidyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-(1-(2-Oxo)pyrrolidinyl)phenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Aminosulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(5-(1-Oxo)indanyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(3-(6-(1-Pyrrolyl)pyridyl)carboxamido)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazolyl)-phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(2-(5-Methyl-1,3,4-oxadiazolyl)phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(3-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Pyridyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(2-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(2-(5-(2-Pyridyl)thienylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-pyridyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(Phenylbenzoylamino)butyl)-7-(3-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-Ethoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-(2-Cyanophenoxy)-2-(4-(4-phenylbenzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline;7-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;7-Cyano-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluommethyl-1,2,3,4-tetrahydroisoquinoline;or a salt thereof.
 6. A process for preparing a compound of formula (I)as defined in claim 1 which process comprises:(a) reacting a compound offormula (II): ##STR12## wherein R¹ and q are as defined in claim 1; witha compound of formula (III): ##STR13## wherein R², Y, Ar and Ar¹ are asdefined in claim 1; (b) reacting a compound of formula (IV): ##STR14##wherein R¹ and R² are as defined in claim 1; with a compound of formula(V):

    Ar.sup.1 --Y--ArCOX                                        Formula (V)

wherein Y, Ar and Ar¹ are as defined in claim 1 and X is a halogen atomor the residue of an activated ester; (c) preparing a compound offormula (I) wherein R¹ is Ar² --Z and Z is a bond, reacting a compoundof formula (VI): ##STR15## wherein one R^(1a) represents a group Wwherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or Wis a group M selected from a boron compound or a metal function, andwhen q is 2 the other R^(1a) is R¹ ; with a compound Ar² --W¹, whereinW¹ is a halogen atom or a trifluoromethylsulphonyloxy group when W is agroup M or W¹ is a group M when W is a halogen atom or atrifluoromethylsulphonyloxy group; (d) preparing a compound of formula(I) wherein R¹ is Ar² --Z and Z is O or S, reacting a compound offormula (VII): ##STR16## wherein one R^(1b) represent a group ZH andwhen q is 2 the other R^(1b) represents R¹ ; with a reagent serving tointroduce the group Ar² ; (e) preparing a compound of formula (I) whereY is a bond, reaction of a compound of formula (VIII): ##STR17## whereinR¹, R², Ar and W are as defined in claim 1, with a compound Ar¹ --W¹,wherein W¹ is a halogen atom or a trifluoromethylsulphonyloxy group whenW is a group M, or W¹ is a group M when W is a halogen atom or atrifluoromethylsulphonyloxy group; (f) interconverting one compound offormula (I) to a different compound of formula (I); and optionallythereafter forming a salt of formula (I).
 7. A pharmaceuticalcomposition comprising a compound of formula (I) as claimed in claim 1or a physiologically acceptable salt thereof and a physiologicallyacceptable carrier therefor.
 8. A method of treating a condition whichrequires modulation of a dopamine receptor which comprises administeringto a subject in need thereof an effective amount of a compound offormula (I) as claimed in claim 1 or a physiologically acceptable saltthereof.
 9. The method according to claim 8 wherein the dopaminereceptor is a dopamine D₃ receptor.
 10. The method according to claim 8wherein a dopamine antagonist is required.
 11. The method according toclaim 8 wherein the condition is a psychotic condition.